The H7N9 avian influenza (AI) virus first emerged in 2013 as a low pathogenic (LPAI) strain, and has repeatedly caused human infection resulting in severe respiratory illness and a mortality of ~38% (>600 deaths) across five epidemic waves. The H7N9 virus has circulated in poultry with little to no discernible clinical signs, making detection and control difficult. Nevertheless, with the potential for further re-assortment and human-to-human transmission, the WHO has identified it as a significant pandemic threat.

Contrary to published data, our group has observed a subset of SPF chickens infected with an egg passaged H7N9 virus succumb to disease, showing signs consistent with highly pathogenic AI (HPAI). Extensive testing for other avian pathogens showed that our results were not due to co-infections. Viral genome sequencing revealed two key mutations had occurred following infection: a change in receptor binding affinity in the HA (226 L>Q), as well as a change in the NP protein (373 A>T). Importantly, we found no multiple basic cleavage site inserted in the HA gene. We further investigated the impact of the NP mutation and demonstrated the viral isolate bearing the mutation was able to cause HPAI-like disease in some chickens.

Intriguingly, again only a subset of chickens succumbed to disease, with the remaining chickens showing no clinical signs. Susceptible birds demonstrated a distinct loss of CD8 T cells from the periphery as well as a dysregulation of IFNγ that was not observed for resistant birds. We further investigated the difference between resistant/susceptible birds and discovered a SNP correlating to increased susceptibility to disease. These data have broad ramifications for our understanding of the pathobiology of HPAI in birds and humans and provide an excellent model for investigating the role of antiviral genes in a natural host species.